Several types of cancers, like pancreatic cancer, have been shown to be particularly dependent on autophagy for growth and survival. This project aims to develop potent, selective and bioavailable small molecule inhibitors of ULK1, an enzyme that initiates autophagy, to enable translation of the hypothesis: autophagy inhibition via ULK1 is a valid therapeutic approach for pancreatic cancer. During this period, the collaborative team fully evaluated several known inhibitors from the literature, prioritizing them for hit-to-lead development. The top inhibitor was selected for preliminary SAR assessments and hit-to-lead evaluation. This chemotype has undergone two rounds of systematic structural exploration to address physicochemical liabilities, as well as to improve potency and selectivity. A subset of our top molecules have advanced into cell-based studies for efficacy evaluation.